Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts
| العنوان: | Promising Therapeutic Efficacy of GC1118, an Anti-EGFR Antibody, against KRAS Mutation-Driven Colorectal Cancer Patient-Derived Xenografts |
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| المؤلفون: | Jae-Chul Lee, Hye Won Lee, Yangmi Lim, Yeri Lee, Minkyu Hur, Eunju Son, Yejin Kim, Do Hyun Nam, Donggeon Kim, Kyoungmin Lee |
| المصدر: | International Journal of Molecular Sciences Volume 20 Issue 23 |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Colorectal cancer, Cetuximab, medicine.disease_cause, KRAS mutation, Mice, Phosphatidylinositol 3-Kinases, PI3K/mTOR/AKT inhibitor, Tumor Cells, Cultured, Epidermal growth factor receptor, Spectroscopy, biology, TOR Serine-Threonine Kinases, General Medicine, EGFR-targeting therapeutic antibody, Computer Science Applications, ErbB Receptors, Female, KRAS, Colorectal Neoplasms, medicine.drug, Signal Transduction, patient-derived xenograft, Transplantation, Heterologous, Mice, Nude, colorectal cancer, Antibodies, Monoclonal, Humanized, Catalysis, Article, Inorganic Chemistry, Proto-Oncogene Proteins p21(ras), medicine, Panitumumab, Animals, Humans, Physical and Theoretical Chemistry, Autocrine signalling, Molecular Biology, Protein kinase B, neoplasms, Protein Kinase Inhibitors, PI3K/AKT/mTOR pathway, business.industry, Organic Chemistry, medicine.disease, digestive system diseases, Mutation, Cancer research, biology.protein, business, Proto-Oncogene Proteins c-akt |
| الوصف: | Epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies, including cetuximab and panitumumab, are used to treat metastatic colorectal cancer (mCRC). However, this treatment is only effective for a small subset of mCRC patients positive for the wild-type KRAS GTPase. GC1118 is a novel, fully humanized anti-EGFR IgG1 antibody that displays potent inhibitory effects on high-affinity EGFR ligand-induced signaling and enhanced antibody-mediated cytotoxicity. In this study, using 51 CRC patient-derived xenografts (PDXs), we showed that KRAS mutants expressed remarkably elevated autocrine levels of high-affinity EGFR ligands compared with wild-type KRAS. In three KRAS-mutant CRCPDXs, GC1118 was more effective than cetuximab, whereas the two agents demonstrated comparable efficacy against three wild-type KRAS PDXs. Persistent phosphatidylinositol-3-kinase (PI3K)/AKT signaling was thought to underlie resistance to GC1118. In support of these findings, a preliminary improved anti-cancer response was observed in a CRC PDX harboring mutated KRAS with intrinsically high AKT activity using GC1118 combined with the dual PI3K/mammalian target of rapamycin (mTOR)/AKT inhibitor BEZ-235, without observed toxicity. Taken together, the superior antitumor efficacy of GC1118 alone or in combination with PI3K/mTOR/AKT inhibitors shows great therapeutic potential for the treatment of KRAS-mutant mCRC with elevated ratios of high- to low-affinity EGFR ligands and PI3K-AKT pathway activation. |
| وصف الملف: | application/pdf |
| تدمد: | 1422-0067 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3ad9e7fdaadf0a4c10812d07b086f36c https://pubmed.ncbi.nlm.nih.gov/31771279 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....3ad9e7fdaadf0a4c10812d07b086f36c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14220067 |
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